Pharmaceutical composition for oral administration comprising high concentration taxane

Pharmaceutical composition for oral administration comprising high concentration taxane
US11020370

The present invention provides a pharmaceutical composition for oral administration, comprising (a) 4 to 40% by weight of a taxane, (b) 10 to 30% by weight of a medium chain triglyceride, (c) 30 to 70% by weight of monooleoyl glycerol, (d) 5 to 30% by weight of a surfactant, and (e) 10 to 30% by weight of polyoxyl glyceryl fatty acid ester and a process for preparing the same.

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Patent 11020370
Priority Jul 30 2015
Filed Apr 06 2016
Issued Jun 01 2021
Expiry Jun 09 2036 Extension 64 days
Inventors Lee, In-Hy…
Assg.orig DAE HWA PH…
Assg.curr DAE HWA PH…
Entity Small
Referenced by 0
References 8
Maint.: currently ok

TECHNICAL FIELD
BACKGROUND ART
DISCLOSURE
Technical Problem
Technical Solution
Advantageous Effects
DESCRIPTION OF DRAWI…
BEST MODE
Example 1
Docetaxel-Containing…
Example 2
Example 3
Example 4
Example 5
Example 6
Example 7
Example 8
Example 9
Example 10
Example 11
Example 12
Example 13
Example 14
Example 15
Example 16
Example 17
Example 18
Example 19
Example 20
Example 21
Paclitaxel-Containin…
Example 22
Example 23
Example 24
Example 25
Example 26
Example 27
Example 28
Example 29
Example 30
Example 31
Example 32
Example 33
Example 34
Example 35
Example 36
Example 37
Example 38
Example 39
Example 40
Example 41
Paclitaxel-Containin…
Comparative Example 1
Comparative Example 2
Experimental Example…
Stability Evaluation…

1. A soft capsule filled with a clear solution consisting of:

(a) 4 to 40% by weight of paclitaxel or docetaxel,

(b) 10 to 30% by weight of a medium chain triglyceride selected from the group consisting of triacetin, tripropionin, tributyrin, trivalerin, tricaproin, tricaprylin, tricaprin, triheptanoin, trinonanoin, triundecanoin, trilaurin, tritridecanoin, trimyristin, tripentadecanoin, tripalmitin, glyceryl triheptadecanoate, and triolein,

(d) 5 to 30% by weight of polyoxyethylene (80) sorbitan monooleate as a surfactant, and

(e) 10 to 30% by weight of polyoxyl glyceryl fatty acid ester selected from the group consisting of caprylocaproyl polyoxyl glyceride, lauroyl polyoxyl glyceride, and stearoyl polyoxyl glyceride.

2. The soft capsule according to claim 1, wherein the polyoxyl glyceryl fatty acid ester is one or more selected from the group consisting of caprylocaproyl polyoxyl-32 glyceride, lauroyl polyoxyl-32 glyceride, and stearoyl polyoxyl-32 glyceride.

3. The soft capsule according to claim 1, consisting of 4 to 25% by weight of paclitaxel or docetaxel, 10 to 20% by weight of the medium chain triglyceride, 40 to 60% by weight of monooleoyl glycerol, 10 to 25% by weight of polyoxyethylene (80) sorbitan monooleate, and 10 to 20% by weight of the polyoxyl glyceryl fatty acid ester.

TECHNICAL FIELD

The present invention relates to a pharmaceutical composition for oral administration comprising a taxane in a high concentration. More specifically, the present invention relates to a taxane-containing pharmaceutical composition for oral administration comprising polyoxyl glyceryl fatty acid ester.

BACKGROUND ART

Taxanes, which are an anticancer agent showing their anti-proliferative effect by acting on the organization of the microtubules in the cellular cytoskeletal system (Huizing M. T. et al., Cancer Inv., 1995, 13: 381-404), are known to exhibit excellent cytotoxicity against various kinds of cancers such as ovarian cancer, breast cancer, esophagus cancer, melanoma and leukemia. Parenteral dosage forms of paclitaxel and docetaxel are commercially available under the trademarks Taxol™ and Taxotere™, respectively. Since a taxane is known to have very low water solubility, the currently available paclitaxel-containing formulation, e.g., Taxol™, has been formulated into the form of emulsion preconcentrate, which is diluted before using for injection. However, in order to overcome the problems related to patient compliance due to the use of the injection form, stability of the formulation, and safety to the human body, etc., researches on the formulations for oral administration are being carried out.

Meanwhile, it has been reported that the oral administration of a taxane such as paclitaxel exhibits very low oral bioavailability due to the action of an outwardly directed efflux pump (Walle et al, Drug Metabo. Disp. 26(4): 343-346 (1998)). It has been also reported that the orally administered paclitaxel is very poorly absorbed (less than 1%) (Eiseman et al, Second NCI Workshop on Taxol and Taxus (sept. 1992), Suffness (ed.) et al, Taxol™ Science and Applications, CRC Press (1995)). As an attempt to improve such a low oral bioavailability, Korean Patent Publication No. 10-2004-0009015 has disclosed a solubilized taxane-containing composition for oral administration, which is formulated by using a medium chain triglyceride such as triacetin, a monoglyceride such as monoolein, and a surfactant such as Tween. Said composition is a solubilized taxane-containing composition for oral administration, whose bioavailability is increased through high mucoadhesive property in the intestine by the monoglyceride such as monoolein. And also, Korean Patent Publication No. 10-2007-0058776 has disclosed an improved process for preparing the solubilized taxane-containing composition for oral administration, the process comprising dissolving paclitaxel, along with a medium chain triglyceride, a monoglyceride, and surfactant, in an organic solvent.

Solid formulations such as soft capsules have advantages in terms of the ease of use, compared to the lipid solution form. Considering the patient's compliance, it is necessary to control the size of the soft capsules to an appropriate size. Therefore, in order to prepare a soft capsule containing the therapeutically effective amount of a taxane, it is required to prepare a lipid solution containing the taxane in a high concentration. However, when a taxane is contained in a high concentration (for example, 4% by weight or more) according to conventional formulation methods (e.g., Korean Patent Publication Nos, 10-2004-0009015 and 10-2007-0058776), the taxane is precipitated from the lipid solution and thus the completely solubilized lipid solution cannot be obtained, thereby leading to the problem of decreased bioavailability.

DISCLOSURE

Technical Problem

The present inventors carried out various researches in order to develop a pharmaceutical composition for oral administration, for example in a capsule form, comprising a taxane in a high concentration. The present inventors have found that, when formulation processes are performed by adding polyoxyl glyceryl fatty acid ester additionally to the conventional paclitaxel-containing compositions (e.g., the compositions prepared according to Korean Patent Publication Nos. 10-2004-0009015 and 10-2007-0058776), a clear solution containing a taxane in a high concentration can be obtained, thereby being able to be formulated into a capsule form such as a soft capsule without the formation of a precipitate.

Therefore, it is an object of the present invention to provide a taxane-containing pharmaceutical composition for oral administration which is formulated by using polyoxyl glyceryl fatty acid ester as a solubilizing agent.

And also, it is another object of the present invention to provide a process for preparing the pharmaceutical composition for oral administration.

Technical Solution

In accordance with an aspect of the present invention, there is provided a pharmaceutical composition for oral administration, comprising (a) 4 to 40% by weight of a taxane, (b) 10 to 30% by weight of a medium chain triglyceride, (c) 30 to 70% by weight of monooleoyl glycerol, (d) 5 to 30% by weight of a surfactant, and (e) 10 to 30% by weight of polyoxyl glyceryl fatty acid ester.

In an embodiment, the polyoxyl glyceryl fatty acid ester may be one or more selected from the group consisting of caprylocaproyl polyoxyl glyceride, lauroyl polyoxyl glyceride, and stearoyl polyoxyl glyceride.

In accordance with another aspect of the present invention, there is provided a process for preparing a pharmaceutical composition for oral administration, comprising (i) dissolving 4 to 40% by weight of a taxane and 10 to 30% by weight of polyoxyl glyceryl fatty acid ester in an organic solvent, (ii) removing the organic solvent from the solution obtained in Step (i), followed by mixing 10 to 30% by weight of a medium chain triglyceride, 30 to 70% by weight of monooleoyl glycerol, and 5 to 30% by weight of a surfactant therewith to form a solution, and (iii) optionally, filling the solution obtained in Step (ii) in a capsule.

In accordance with still another aspect of the present invention, there is provided a process for preparing a pharmaceutical composition for oral administration, comprising (i′) dissolving 4 to 40% by weight of a taxane, 10 to 30% by weight of a medium chain triglyceride, 30 to 70% by weight of monooleoyl glycerol, 5 to 30% by weight of a surfactant, and 10 to 30% by weight of polyoxyl glyceryl fatty acid ester in an organic solvent, (ii′) removing the organic solvent from the solution obtained in Step (i′), and (iii′) optionally, filling the solution obtained in Step (ii′) in a capsule.

Advantageous Effects

It has been found by the present invention that, when formulation processes are performed by adding polyoxyl glyceryl fatty acid ester to a lipid solution comprising a taxane, a medium chain triglyceride, monooleoyl glycerol, and a surfactant, a clear solution containing a taxane in a high concentration can be obtained, thereby being able to be formulated into a capsule form such as a soft capsule without the formation of a precipitate. Therefore, the pharmaceutical composition for oral administration according to the present invention makes it possible to formulate into solid formulations such as soft capsules.

DESCRIPTION OF DRAWINGS

FIG. 1 represents the appearances of the docetaxel-containing lipid solutions prepared in Example 1 and Comparative Example 1. A: the docetaxel-containing lipid solution prepared in Example 1, B: the docetaxel-containing lipid solution prepared in Comparative Example 1.

FIG. 2 represents the appearances of the paclitaxel-containing lipid solutions prepared in Example 21 and Comparative Example 2. A: the paclitaxel-containing lipid solution prepared in Example 21, B: the paclitaxel-containing lipid solution prepared in Comparative Example 2.

BEST MODE

The polyoxyl glyceryl fatty acid ester may be one or more selected from the group consisting of caprylocaproyl polyoxyl glyceride, lauroyl polyoxyl glyceride, and stearoyl polyoxyl glyceride. Preferably, the polyoxyl glyceryl fatty acid ester may be one or more selected from the group consisting of caprylocaproyl polyoxyl-32 glyceride (e.g., LABRASOL™, etc.), lauroyl polyoxyl-32 glyceride (e.g., Gelucire™ 44/14, etc.), and stearoyl polyoxyl-32 glyceride (e.g., Gelucire™ 50/13, etc.).

The taxane includes one or more selected from the group consisting of paclitaxel, docetaxel, 7-epipaditaxel, t-acetylpaclitaxel, 10-desacetylpaclitaxel, 10-desacetyl-7-epipaclitaxel, 7-xylosyl pad itaxel, 10-desacetyl-7-glutarylpaclitaxel, 7-N,N-dimethylglycylpaclitaxel, 7-L-alanylpaclitaxel, and so on. For example, the taxane may be paclitaxel and/or docetaxel.

The medium chain triglyceride means a substance in which three molecules of saturated or unsaturated C₂-C₂₀fatty acids and one molecule of glycerol are linked by ester bond. For example, the medium chain triglyceride includes triacetin, tripropionin, tributyrin, trivalerin, tricaproin, tricaprylin (e.g., Captex™ 8000 etc.), tricaprin, triheptanoin, trinonanoin, triundecanoin, trilaurin, tritridecanoin, trimyristin, tripentadecanoin, tripalmitin, glyceryl triheptadecanoate, triolein, and so on.

The monooleoyl glycerol is also referred to as monoolein. A commercially available monooleoyl glycerol (e.g., Rylo MG 19™, Danisco) may be also used.

The surfactant includes polyoxyethylene-polyoxypropylene block copolymer (e.g., Poloxamer™), sorbitan ester (e.g., Span™), polyoxyethylene sorbitan (e.g., Tween™), polyoxyethylene ether (e.g., Brij™), and so on.

In an embodiment, the pharmaceutical composition of the present invention may comprise 4 to 25% by weight of the taxane, 10 to 20% by weight of the medium chain triglyceride, 40 to 60% by weight of monooleoyl glycerol, 10 to 25% by weight of the surfactant, and 10 to 20% by weight of polyoxyl glyceryl fatty acid ester. The pharmaceutical composition for oral administration is preferably in the form filled in a capsule such as a soft capsule.

In the processes of the present invention, said monooleoyl glycerol, taxane, medium chain triglyceride, surfactant, and polyoxyl glyceryl fatty acid ester are as described above.

In the processes of the present invention, the organic solvent may be one or more selected from the group consisting of a halogenated alkyl compound, an alcohol, and a ketone. The halogenated alkyl compound may be one or more selected from the group consisting of halogenated C₁to C₅alkyl compounds, preferably methylene chloride or chloroform, more preferably methylene chloride. The alcohol may be one or more selected from the group consisting of C₁to C₅lower alcohols, preferably methanol, ethanol or isopropyl alcohol, more preferably ethanol. The ketone may be acetone.

The organic solvent may be used in an amount capable of dissolving the taxane and the medium chain triglyceride, preferably in the amount of 0.4 times to 20 times based on the volume of the medium chain triglyceride, more preferably in the same volume as the volume of the medium chain triglyceride, but is not limited thereto. Said amounts of the organic solvent, which makes it possible to dissolve the taxane such as paclitaxel and docetaxel sufficiently, can reduce the waste originated from the use of excessive amounts of the solvent and the unnecessary effort for removing the organic solvent. In the processes of the present invention, the step for removing the organic solvent may be performed according to conventional drying methods, for example, by drying under reduced pressure at 15 to 50° C., preferably at room temperature. Through performing the steps for dissolving with an organic solvent and removing the organic solvent as described above, it is possible to homogeneously mix the respective components in the resulting composition.

The present invention will be described in further detail with reference to the following examples and experimental examples. These examples and experimental examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example 1

Docetaxel-Containing Soft Capsules

The docetaxel-containing pharmaceutical composition for oral administration was prepared according to the components and amounts shown in Table 1. Docetaxel and LABRASOL™ (Gattefosse) were completely dissolved in ethanol (about 14 times of the volume of tricaprylin). The resulting solution was dried under reduced pressure at 40° C. to remove ethanol. To the resulting mixture, were added tricaprylin (Captex™ 8000, ABITEC), monooleoyl glycerol (Rylo MG 19™, Danisco), and Tween™ 80. The resulting mixture was stirred at 40° C. to obtain the clear oily solution. The resulting clear oily solution was filled into a soft capsule. The appearance of the clear oily solution is shown in FIG. 1 (left, A).

	TABLE 1

				Ratio
			Amount/1	(% by
	L/I	Component	capsule	weight)


1	Taxane	Docetaxel	50	mg	4.84
2	Medium chain triglyceride	Tricaprylin	0.14	ml	12.77
3	Monooleoyl glycerol	Rylo MG 19 ™	0.56	ml	50.65
4	Surfactant	Tween ™ 80	0.16	ml	17.42
5	Polyoxyl glyceryl fatty	LABRASOL ™	0.14	ml	14.32
	acid ester
	Total	100.00

Example 2

The docetaxel-containing pharmaceutical composition for oral administration in the soft capsule form was prepared in accordance with the same procedures as in Example 1, using triacetin (Sigma) instead of tricaprylin.

Paclitaxel-Containing Soft Capsules

The paclitaxel-containing pharmaceutical composition for oral administration was prepared according to the components and amounts shown in Table 2. Paclitaxel and LABRASOL™ (Gattefosse) were completely dissolved in methylene chloride (about 14 times of the volume of tricaprylin). The resulting solution was dried under reduced pressure at 40° C. to remove methylene chloride. To the resulting mixture, were added tricaprylin (Captex™ 8000, ABITEC), monooleoyl glycerol (Rylo MG 19™, Danisco), and Tween™ 80. The resulting mixture was stirred at 40° C. to obtain the clear oily solution. The resulting clear oily solution was filled into a soft capsule. The appearance of the oily solution is shown in FIG. 2 (left, A).

	TABLE 2

				Ratio
			Amount/1	(% by
	L/I	Component	capsule	weight)


1	Taxane	Paclitaxel	50	mg	4.84
2	Medium chain triglyceride	Captex ™ 8000	0.14	ml	12.77
3	Monooleoyl glycerol	Rylo MG 19 ™	0.56	ml	50.65
4	Surfactant	Tween ™ 80	0.16	ml	17.42
5	Polyoxyl glyceryl fatty	LABRASOL ™	0.14	ml	14.32
	acid ester
	Total	100.00

Example 22

The paclitaxel-containing pharmaceutical composition for oral administration in the soft capsule form was prepared in accordance with the same procedures as in Example 21, using anhydrous ethanol instead of methylene chloride.

Paclitaxel-Containing Soft Capsules

The paclitaxel-containing pharmaceutical composition for oral administration was prepared according to the components and amounts shown in Table 3. Paclitaxel and LABRASOL™ (Gattefosse) were completely dissolved in methylene chloride (about 14 times of the volume of tricaprylin). The resulting solution was dried under reduced to pressure at 40° C. to remove methylene chloride. To the resulting mixture, were added tricaprylin (Captex™ 8000, ABITEC), monooleoyl glycerol (Rylo MG 19™, Danisco), and Tween™ 80. The resulting mixture was stirred at 40° C. to obtain the clear oily solution. The resulting clear oily solution was filled into a soft capsule.

	TABLE 3

				Ratio
			Amount/1	(% by
	L/I	Component	capsule	weight)


1	Taxane	Paclitaxel	250	mg	20.55
2	Medium chain triglyceride	Captex ™ 8000	0.14	ml	10.11
3	Monooleoyl glycerol	Rylo MG 19 ™	0.56	ml	43.72
4	Surfactant	Tween ™ 80	0.16	ml	14.05
5	Polyoxyl glyceryl fatty	LABRASOL ™	0.14	ml	11.57
	acid ester
	Total	100.00

Comparative Example 1

The docetaxel-containing composition was prepared according to the components and amounts shown in Table 4. Docetaxel and tricaprylin (Captex™ 8000, ABITEC) were completely dissolved in ethanol (about 14 times of the volume of tricaprylin). The resulting solution was dried under reduced pressure at 40° C. to remove ethanol. To the resulting mixture, were added monooleoyl glycerol (Rylo MG 19™, Danisco) and Tween™ 80. The resulting mixture was stirred at 40° C. to obtain the oily solution. The resulting oily solution was an opaque dispersion having white precipitates. The appearance thereof is shown in FIG. 1 (right, B).

	TABLE 4

				Ratio
			Amount/1	(% by
	L/I	Component	capsule	weight)


1	Taxane	Docetaxel	30	mg	3.01
2	Medium chain triglyceride	Tricaprylin	0.28	ml	26.30
3	Monooleoyl glycerol	Rylo MG 19 ™	0.56	ml	52.49
4	Surfactant	Tween ™ 80	0.16	ml	18.20
	Total	100.00

Comparative Example 2

The paclitaxel-containing composition was prepared according to the components and amounts shown in Table 5. Paclitaxel and tricaprylin (Captex™ 8000, ABITEC) were completely dissolved in methylene chloride (about 14 times of the volume of tricaprylin). The resulting solution was dried under reduced pressure at 40° C. to remove methylene chloride. To the resulting mixture, were added monooleoyl glycerol (Rylo MG 19™, Danisco) and Tween™ 80. The resulting mixture was stirred at 40° C. to obtain the oily solution. The resulting oily solution was an opaque dispersion having white precipitates. The appearance thereof is shown in FIG. 2 (right, B).

	TABLE 5

				Ratio
			Amount/1	(% by
	L/I	Component	capsule	weight)


1	Taxane	Paclitaxel	30	mg	3.01
2	Medium chain triglyceride	Tricaprylin	0.28	ml	26.30
3	Monooleoyl glycerol	Rylo MG 19 ™	0.56	ml	52.49
4	Surfactant	Tween ™ 80	0.16	ml	18.20
	Total	100.00

Experimental Example 1

Stability Evaluation of Gelatin Capsules

The soft capsules prepared in Example 1 and Example 21 were placed in a HDPE bottle, which were then stored under the conditions of 25° C. and 60% (RH) for 6 months to evaluate the stability of the gelatin capsules. Stability of the gelatin capsules was evaluated through observing the appearances thereof and a leak therefrom. The results are shown in the following Table 6.

	TABLE 6

	Example 1	Example 21


1 month	Leak	No leak occurred	No leak occurred
	Appearance	No appearance	No appearance
		changed	changed
3 months	Leak	No leak occurred	No leak occurred
	Appearance	No appearance	No appearance
		changed	changed
6 months	Leak	No leak occurred	No leak occurred
	Appearance	No appearance	No appearance
		changed	changed

From the results of Table 6, it can be seen that the soft capsules prepared according to the present invention have excellent stability.

INVENTORS:

Lee, In-Hyun, Park, Yeong-Taek, Son, Min-Hee, Lee, Han-Koo

THIS PATENT IS REFERENCED BY THESE PATENTS:

Patent

Priority

Assignee

Title

THIS PATENT REFERENCES THESE PATENTS:

Patent	Priority	Assignee	Title
6348491,	Jul 01 1999	National Science Council	Oil-in-water emulsion for encapsulating paclitaxel
8075917,	Jul 20 2002	DAEHWA PHARM CO , LTD	Composition for solubilization of paclitaxel and preparation method thereof
20040092428,
20060104999,
20100310661,
KR1020070058776,
KR20070058776,
WO2013045357,

ASSIGNMENT RECORDS Assignment records on the USPTO

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Executed on	Assignor	Assignee	Conveyance	Frame	Reel	Doc
Apr 06 2016		DAE HWA PHARMA. CO., LTD.	(assignment on the face of the patent)
Jan 16 2018	SON, MIN-HEE	DAE HWA PHARMA CO , LTD	ASSIGNMENT OF ASSIGNORS INTEREST SEE DOCUMENT FOR DETAILS	044763	0430	pdf
Jan 17 2018	LEE, IN-HYUN	DAE HWA PHARMA CO , LTD	ASSIGNMENT OF ASSIGNORS INTEREST SEE DOCUMENT FOR DETAILS	044763	0430	pdf
Jan 19 2018	PARK, YEONG-TAEK	DAE HWA PHARMA CO , LTD	ASSIGNMENT OF ASSIGNORS INTEREST SEE DOCUMENT FOR DETAILS	044763	0430	pdf
Jan 22 2018	LEE, HAN-KOO	DAE HWA PHARMA CO , LTD	ASSIGNMENT OF ASSIGNORS INTEREST SEE DOCUMENT FOR DETAILS	044763	0430	pdf

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